The past few decades have witnessed major advances in our understanding of the pathophysiology of parkinsonism, including the recognition of MPTP-induced parkinsonism (Langston et al. 1983), the discovery of numerous genes responsible for rare Mendelian forms of parkinsonism (Hardy et al. 2009), and the identification of α-synuclein as the primary component of Lewy bodies (LBs) (Spillantini et al. 1997), the hallmark histopathologic lesion of Parkinson’s disease (PD) (Shults 2006). These advances have led to the development of both cellular and animal models that recapitulate key features of PD. These models hold potential for identifying mechanisms of nigrostriatal degeneration and for development of disease-modifying treatments for PD. They have been used in the development of novel neuroprotective strategies, but so far, these discoveries have not successfully translated into clinical use. While the reasons for these failures of translation are debatable (Ahlskog 2007, Waldmeier et al. 2006), it is possible that the pathophysiologic mechanisms of genetic and acute intoxication forms of parkinsonism do not apply to PD. This seems particularly likely for causes of parkinsonism that do not involve the formation of aggregates of insoluble α-synuclein (Hasegawa et al. 2009, Wszolek et al. 2004). Most of the existing models of PD have been developed in young animals, and more emphasis on understanding the changes that occur in the aging nervous system may be necessary. There are probably numerous ways that highly vulnerable mesencephalic dopaminergic neurons can be damaged, not all of which are relevant to PD. Indeed, most of the atypical parkinsonian disorders that also produce nigral degeneration, including progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy involve disease mechanisms, such as accumulation of abnormal tau protein in neurons and glia (Ballatore et al. 2007) or primary α-synuclein pathology in glial cells (Wenning et al. 2008) that may not be relevant to PD. For these reasons, this chapter will focus on the neuropathology of the most common pathologic substrate of parkinsonism, LB disease.
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